Various publications, including patents, published applications, technical articles and scholarly articles are cited throughout the specification. Each of these cited publications is incorporated by reference herein, in its entirety.
Cystic fibrosis (CF) is a recessive genetic disorder with an incidence in approximately one of every 3,500 live births. CF results from a mutation in the cystic fibrosis transmembrane regulator gene, and a resultant impairment in ion transport. The result of these mutations is the secretion of abnormally thick, sticky mucus that obstructs the lungs and airways (Gibson R L et al. (2003) Am. J. Respir. Crit. Care Med. 168:918-51). Abnormalities of ion transport in the airways of CF patients lead to dehydration of airway surface liquid. Airway mucus may then become adherent to airway surfaces, eventually obstruct CF airways, and serve as a substrate for bacterial colonization and chronic infection.
In addition to CF, numerous other chronic or transient pulmonary diseases are characterized by the retention of mucous secretions in the lungs and airways. These include acute or chronic bronchitis and other chronic obstructive pulmonary disease (COPD), bronchiectasis, bronchiolitis, primary or secondary ciliary dyskinesia, asthma, sinusitis and pneumonia.
Pulmonary surfactant (PS) is important for the integrity of the lungs (Griese M et al. (2005) Am. J. Respir. Crit. Care Med. 170:1000-5). Pulmonary surfactants are synthesized by epithelial cells, and are composed of approximately 90% lipids and 10% proteins (Devendra G et al. (2002) Respir. Res. 3:19-22). PS covers the entire alveolar surface of the lungs and the terminal conducting airways leading to the alveoli, and facilitate respiration by continually modifying the surface tension of the fluid normally present within the alveoli. By lowering the surface tension of the terminal conducting airways, surfactant maintains patency, i.e., keeps airways open (Griese M (1999) Eur. Respir. J. 13:1455-76). Loss of patency leads to obstruction of the airway and compromised pulmonary function. In humans, PS primarily contains phospholipids and four surfactant polypeptides, referred to as SP-A, SP-B, SP-C and SP-D (Tierney D F et al. (1989) Am. J. Physiol. 257:L1-L12; and, Griese M (1999) Eur. Respir. J. 13:1455-76). SP-A, -B, and -C are important for lowering surface tension. In humans, the absence of SP-B is fatal. SP-A aids in resistance against inhibition of surfactant activity by inflammatory mediators and products (Griese M et al. (2005) Respir. Res. 6:133-42). SP-D facilitates phagocytosis of pathogens, and has immunomodulatory, anti-inflammatory, and antioxidative properties (Clark H et al. (2003) Arch. Dis. Child 88:981-4).
Natural and synthetic pulmonary surfactants have been studied for their potential to treat various pulmonary disorders, including asthma, bronchiolitis, chronic bronchitis, cystic fibrosis, pneumonia, and neonatal respiratory distress syndrome, among others (Griese M (1999) Eur. Respir. J. 13:1455-76). In most cases, some measurable improvement in the patients' conditions was noted, although treatment of CF patients with a bovine surfactant extract resulted in no improvement in lung function or oxygenation, due at least in part to insufficient deposition of the PS in the patients' lungs (Griese M et al. (1997) Eur. Respir. J. 10:1989-97). In contrast, treatment with aerosolized surfactant lipid palmitoylphosphadidylcholine (DPPC) was reported to improve pulmonary function and sputum transportability in patients with chronic bronchitis (Anzueto A et al. (1997), J. Am. Med. Assoc. 278:1426-1431).
Hyperosmolar solutions and aerosols have been used to promote clearance of mucous secretions from the airways, thereby improving lung function. For example, hyperosmolar dry powder mannitol was reported to improve pulmonary function in adults subjects with non-CF bronchiectasis, and to reduce the surface adhesivity and increase cough clearance of expectorated sputum (Daviskas E, et al. (2005) Respirology 10:46-56). Administration of hypertonic saline (1M) to CF patients via inhalation was reported to facilitate mucus clearance and improve lung function in the patients (see, e.g., Donaldson SH et al. (2006) N. Engl. J. Med. 354:241-50). However, the action of hypertonic saline is short-lived, and hypertonic saline by itself failed to restore the patency of many obstructed airways in the patients (Elkins M R et al. (2006) N. Engl. J. Med. 354:229-40). In addition, hypertonic saline inhalation can produce bronchoconstriction in some patients, and may potentiate inflammation (Didier C et al. (2001) Chest 120:1815-21; and, Suri R et al. (2002) Am. J. Respir. Crit. Care Med 166:352-5). As such, there is a need for therapies for CF and other such pulmonary disorders that enhance mucus clearance and lung function in patients and concomitantly restore airway patency, with limited negative side effects.